Study to Evaluate the Effects of Panitumumab if Combined With Chemotherapy for 2nd Treatment of Colorectal Cancer
Ontology highlight
ABSTRACT:
DISEASE(S): Metastatic Colorectal Cancer,Colorectal Neoplasms,Metastatic Colorectal Cancer (mcrc),Cancer
PROVIDER: 2076032 | ecrin-mdr-crc |
REPOSITORIES: ECRIN MDR
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Project description:Primary objectives: Assessing in patients with metastatic colorectal cancer refractory to treatment with chemotherapy and Irinotecan 5FU the correlation between the response to treatment with Cetuximab in combination with chemotherapy based Irinotecan;search for mutations of K-RAS and odetermination of PTEN by immunohistochemistry;Gene amplification dell’EGFR determined by FISH;the intensity of expression dell’EGFR determined by immunohistochemistry test with DAKO and Zymed (monoclonal antibody clone 31G7)
| 2525001 | ecrin-mdr-crc
Project description:Bianconi2012 - EGFR and IGF1R pathway in lung cancer
EGFR and IGF1R pathways play a key role in various human cancers and are crucial for tumour transformation and survival of malignant cells. High EGFR and IGF1R expression and activity has been associated with multiple aspects of cancer progression including tumourigenesis, metastasis, resistance to chemotherapeutics and other molecularly targeted drugs. Here, the biological relationship between the proteins involved in EGFR and IGF1R pathways and the downstream MAPK and PIK3 networks has been modelled to study the time behaviour of the overall system, and the functional interdependencies among the receptors, the proteins and kinases involved.
This model is described in the article:
Computational model of EGFR and IGF1R pathways in lung cancer: a Systems Biology approach for Translational Oncology.
Bianconi F, Baldelli E, Ludovini V, Crinò L, Flacco A, Valigi P.
Biotechnol Adv. 2012 Jan-Feb;30(1):142-53.
Abstract:
In this paper we propose a Systems Biology approach to understand the molecular biology of the Epidermal Growth Factor Receptor (EGFR, also known as ErbB1/HER1) and type 1 Insulin-like Growth Factor (IGF1R) pathways in non-small cell lung cancer (NSCLC). This approach, combined with Translational Oncology methodologies, is used to address the experimental evidence of a close relationship among EGFR and IGF1R protein expression, by immunohistochemistry (IHC) and gene amplification, by in situ hybridization (FISH) and the corresponding ability to develop a more aggressive behavior. We develop a detailed in silico model, based on ordinary differential equations, of the pathways and study the dynamic implications of receptor alterations on the time behavior of the MAPK cascade down to ERK, which in turn governs proliferation and cell migration. In addition, an extensive sensitivity analysis of the proposed model is carried out and a simplified model is proposed which allows us to infer a similar relationship among EGFR and IGF1R activities and disease outcome.
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2012-11-20 | BIOMD0000000427 | BioModels
Project description:Primary objectives: To compare in skin biopsies the effects of an cetuximab dose escalation regimen on EGFR and downstream signaling pathway markers with those of the standard cetuximab regimen
Primary endpoints: Expression of EGFR and markers for the downstream signalling pathways in normal skin expressed by means of percentage of stained cells and staining intensity. IHC staining will allow a semi quantitative analysis of protein markers of the EGFR related signalling pathway.
| 2515542 | ecrin-mdr-crc
Project description:Intimal sarcoma (IS) is a rare, malignant and aggressive tumor that shows a relentless course with a concomitant low survival rate, for which no effective treatment is available. In this study, 21 cases of large arterial blood vessel IS were analyzed by immunohistochemistry and fluorescent in situ hydridisation (FISH), and selectively by karyotyping, array-CGH, sequencing, phospho-kinase antibody arrays and Western immunoblotting, in search for the novel diagnostic markers and potential molecular targets. Ex vivo immunoassays were applied to test the sensitivity of IS primary tumor cells to the receptor tyrosine kinase (RTK) inhibitors imatinib and dasatinib.We demonstrated that amplification of the platelet-derived growth factor receptor alpha (PDGFRA) is a common finding in IS, and might be considered as a cytogenetic hallmark of this entity. This amplification is consistently associated with PDGFRA activation. Furthermore, the tumors reveal persistent activation of the epidermal growth factor receptor (EGFR), concurrent to PDGFRA activation. Activated PDGFRA and EGFR frequently co-exist with amplification and overexpression of MDM2. Ex vivo immunoassays on primary cells showed the potency of dasatinib to inhibit PDGFRA and downstream effectors in IS. Our findings provide a rationale for investigating therapies that target PDGFRA, EGFR or MDM2 in IS. Given the molecular heterogeneity of this tumor type and the potential crosstalk between PDGFRA and EGFR signaling pathways, targeting multiple RTKs and aberrant downstream effectors might be required to improve therapeutic outcome for patients with this disease. Key words: intimal sarcoma, PDGFRA, EGFR, MDM2, targeted therapy, amplification
2010-05-20 | GSE21530 | GEO
Project description:Interventions: A group:Before using cetuximab;B group:After progression of disease:no
Primary outcome(s): KRAS gene sequence;NRAS gene sequence;BRAF gene sequence;PIK3CA gene sequence;EGFR gene sequence;EGFR gene copy numbers;EGFR expression;Her2 expression;c-Met expression;PTEN expression
Study Design: historical control
| 2671639 | ecrin-mdr-crc
Project description:EGFR mutant non-small cell lung cancer patients disease demonstrates remarkable responses to EGFR targeted therapy, but inevitably they succumb to acquired resistance, which can be complex and difficult to treat. Analyzing acquired resistance through broad molecular testing is crucial to understanding the resistance mechanisms and developing new treatment options. We performed diverse clinical testing on a patient with successive stages of acquired resistance, first to an EGFR inhibitor with MET gene amplification and then subsequently to combination EGFR and MET targeted therapies. A patient-derived cell line obtained at the time of disease progression was used to identify NRAS gene amplification as an additional driver of drug resistance to combination EGFR/MET therapies. Analysis of downstream signaling revealed ERK activation that could only be eliminated by trametinib treatment, while Akt activation could be modulated by various combinations of MET, EGFR and PI3K inhibitors. Combination of an EGFR inhibitor with a MEK inhibitor was identified as a possible treatment option to overcome drug resistance related to NRAS gene amplification.
2021-07-28 | GSE180894 | GEO
Project description:Although the oncogenic signalings driven by amplification and mutations of EGF receptor (EGFR) gene play a major role in glioblastoma pathogenesis, the responsible downstream mechanisms remain less clear. Here we demonstrate that tripartite motif-containing protein 59 (TRIM59), acting as a new downstream effector of EGFR signaling, regulates STAT3 activation in glioblastoma. EGFR signaling leads to TRIM59 upregulation through SOX9 that results in enhancing TRIM59 interaction with STAT3 in nucleus, and inhibiting STAT3 association with TC45 (the nuclear form of T cell protein tyrosine phosphatase TC-PTP), thereby maintaining STAT3 phosphorylation and activation and promoting tumorigenesis. Silencing TRIM59 suppresses cell proliferation, migration, and orthotopic xenograft brain tumorigenesis of GBM cells. Moreover, evaluation of GBM patient samples reveals an association among EGFR activation, TRIM59 expression, STAT3 phosphorylation, and poor prognoses. Our study identifies TRIM59 as a new regulator of oncogenic EGFR-STAT3 signaling and a potential therapeutic target for GBM patients with EGFR activation.
2019-03-26 | GSE106557 | GEO
Project description:The model is based on publication:
Mathematical analysis of gefitinib resistance of lung adenocarcinoma caused by MET amplification
Abstract:
Gefitinib, one of the tyrosine kinase inhibitors of epidermal growth factor receptor (EGFR), is effective for treating lung adenocarcinoma harboring EGFR mutation; but later, most cases acquire a resistance to gefitinib. One of the mechanisms conferring gefitinib resistance to lung adenocarcinoma is the amplification of the MET gene, which is observed in 5–22% of gefitinib-resistant tumors. A previous study suggested that MET amplification could cause gefitinib resistance by driving ErbB3-dependent activation of the PI3K pathway. In this study, we built a mathematical model of gefitinib resistance caused by MET amplification using lung adenocarcinoma HCC827-GR (gefitinib resistant) cells. The molecular reactions involved in gefitinib resistance consisted of dimerization and phosphorylation of three molecules, EGFR, ErbB3, and MET were described by a series of ordinary differential equations. To perform a computer simulation, we quantified each molecule on the cell surface using flow cytometry and estimated unknown parameters by dimensional analysis. Our simulation showed that the number of active ErbB3 molecules is around a hundred-fold smaller than that of active MET molecules. Limited contribution of ErbB3 in gefitinib resistance by MET amplification is also demonstrated using HCC827-GR cells in culture experiments. Our mathematical model provides a quantitative understanding of the molecular reactions underlying drug resistance.
2019-09-30 | BIOMD0000000827 | BioModels
Project description:Background: Glioblastoma mortality is driven by tumour progression or recurrence despite administering a therapeutic arsenal consisting of surgical resection, radiation, and alkylating chemotherapy. The genetic changes underlying tumour progression and chemotherapy resistance are poorly understood. Methods: In this work, we sought to define the relationship between EGFR amplification status, EGFR mRNA expression, and EGFR pathway activity. We compared RNA-sequencing data from matched primary and recurrent tumour samples (N = 40 patients, 20 with EGFR amplification). Results: In the setting of glioblastoma recurrence, the EGFR pathway was overexpressed regardless of EGFR amplification status, suggesting a common genomic endpoint in recurrent glioblastoma, although EGFR amplification did associate with higher EGFR mRNA expression. Three of forty patients in the study cohort had EGFR-amplified tumours and received targeted EGFR therapy. Their molecular subtypes and clinical outcomes did not significantly differ from patients who received conventional chemotherapy. Conclusion: Our findings suggest that while the EGFR amplification may confer a unique molecular profile in primary glioblastoma, pathway analysis reveals upregulation of the EGFR pathway in recurrence, regardless of amplification status. As such, the EGFR pathway may be a key mediator of glioblastoma progression.
2023-01-25 | GSE222515 | GEO
Project description:<h4><strong>INTRODUCTION:</strong> The identification of frequent acquired mutations shows that patients with oligodendrogliomas have divergent biology with differing prognoses regardless of histological classification. A better understanding of molecular features as well as their metabolic pathways is essential.</h4><h4><strong>OBJECTIVES: </strong>The aim of this study was to examine the relationship between the tumor metabolome, six genomic aberrations (isocitrate dehydrogenase1 [IDH1] mutation, 1p/19q codeletion, tumor protein p53 [TP53] mutation, O<sup>6</sup>-methylguanin-DNA methyltransferase [MGMT] promoter methylation, epidermal growth factor receptor [EGFR] amplification, phosphate and tensin homolog [PTEN] methylation), and the patients' survival time.</h4><h4><strong>METHODS:</strong> We applied <sup>1</sup>H high-resolution magic-angle spinning (HRMAS) nuclear magnetic resonance (NMR) spectroscopy to 72 resected oligodendrogliomas.</h4><h4><strong>RESULTS:</strong> The presence of IDH1, TP53, 1p19q codeletion, MGMT promoter methylation reduced the relative risk of death, whereas PTEN methylation and EGFR amplification were associated with poor prognosis. Increased concentration of 2-hydroxyglutarate (2HG), N-acetyl-aspartate (NAA), myo-inositol and the glycerophosphocholine/phosphocholine (GPC/PC) ratio were good prognostic factors. Increasing the concentration of serine, glycine, glutamate and alanine led to an increased relative risk of death.</h4><h4><strong>CONCLUSION:</strong> HRMAS NMR spectroscopy provides accurate information on the metabolomics of oligodendrogliomas, making it possible to find new biomarkers indicative of survival. It enables rapid characterization of intact tissue and could be used as an intraoperative method.</h4>
2021-10-06 | MTBLS869 | MetaboLights